Sex/Gender Factors in Nicotine Addiction

描述（由申请人提供）：这是针对PA-07-329提交的题为“尼古丁成瘾中的性别/性别因素”的修订申请。吸烟是最普遍的成瘾性疾病之一，与许多使人衰弱的疾病（如肺癌、中风、心血管和呼吸系统疾病、骨质疏松症）有关，每年估计造成438 000人死亡。性别和性别因素对尼古丁成瘾的了解甚少，我们假设荷尔蒙环境是吸烟滥用相关影响的一个关键影响因素。我们建议进行临床前行为研究，以确定性别和月经周期阶段如何影响尼古丁的自我给药，以及急性和慢性使用神经活性性腺类固醇激素（雌二醇、睾酮和孕酮）如何改变尼古丁的强化作用。非人类灵长类动物是自我给药的优秀模型，猕猴月经周期的神经内分泌控制与女性非常相似。尼古丁的自我给药将维持一个渐进的比例计划，这需要对连续的尼古丁注射增加反应的数量。因变量将是自我注射尼古丁的次数、有效反应的比率和递进比率“断点”，即动物停止对尼古丁反应的比率。在旨在检查性别和月经周期对尼古丁自我给药的影响的研究中，将测量黄体酮和雌二醇水平，以客观地确定月经周期的阶段，并区分排卵和不排卵月经周期。我们假设女性会自我服用更多的尼古丁，并且在递进比率时间表上比男性达到更高的断点。接下来，我们将研究神经活性性腺类固醇激素（雌二醇、睾酮和黄体酮）的急性和慢性治疗对基础类固醇激素水平较低的性腺切除术男性和女性尼古丁自我给药的剂量效应曲线的影响。我们假设雌二醇和睾酮会增强尼古丁的强化作用，而黄体酮会在女性中比男性更大程度地减弱尼古丁的强化作用。类固醇激素受体拮抗剂将用于确定观察到的行为效应的激素特异性。最后，比较性腺切除术前后单独使用性腺类固醇激素对男性和女性的强化作用。神经活性类固醇激素为治疗许多精神疾病和药物滥用提供了一种新的方法。拟议的研究可能会转化为新的和更有效的治疗尼古丁成瘾的方法，并将推进我们对其基本神经生物学的理解。公共卫生相关性：吸烟成瘾是一个重大的公共卫生问题，与许多使人衰弱和致命的疾病（肺癌、中风、心血管和呼吸系统疾病、骨质疏松症）有关，但有效的治疗方法仍然难以捉摸。我们建议研究性和神经活性性腺类固醇如何影响尼古丁（烟草的主要成瘾成分）在男性和女性中的滥用相关效应。我们假设神经活性性腺类固醇激素可能为治疗尼古丁成瘾提供一种新的生物学方法，部分原因是这些神经活性激素被用于治疗许多精神疾病，包括抑郁症和焦虑症，并且可能在药物依赖方面有治疗应用。

DESCRIPTION (provided by applicant): This is a revised application entitled "Sex/Gender Factors in Nicotine Addiction" submitted in response to PA-07-329. Cigarette smoking is one of the most prevalent addictive disorders and is associated with a number of debilitating diseases (e.g., lung cancer, stroke, cardiovascular and respiratory disease, osteoporosis) that result in an estimated 438,000 deaths each year. Sex and gender factors in nicotine addiction are poorly understood, and we hypothesize that the hormonal milieu is one critical influence on the abuse-related effects of smoking. We propose preclinical behavioral studies to determine how sex and menstrual cycle phase influence nicotine self-administration, and how acute and chronic treatment with neuroactive gonadal steroid hormones (estradiol, testosterone and progesterone) alters the reinforcing effects of nicotine. Nonhuman primates are excellent models of drug self-administration and neuroendocrine control of the macaque menstrual cycle is very similar to that of women. Nicotine self- administration will be maintained on a progressive-ratio schedule that requires an increasing number of responses for successive nicotine injections. The dependent variables will be the number of nicotine injections self-administered, the rate of operant responding, and the progressive ratio "break point", i.e., the ratio at which animals stop responding for nicotine. In studies designed to examine the influence of sex and the menstrual cycle on nicotine self- administration, progesterone and estradiol levels will be measured to objectively define phases of the menstrual cycle and to distinguish between ovulatory and anovulatory menstrual cycles. We hypothesize that females will self-administer more nicotine and reach higher break points on a progressive ratio schedule than males. Next, we will examine the effects of acute and chronic treatment with neuroactive gonadal steroid hormones (estradiol, testosterone and progesterone) on nicotine self-administration dose-effect curves in gonadectomized males and females where basal steroid hormone levels are low. We hypothesize that estradiol and testosterone will enhance the reinforcing effects of nicotine, and that progesterone will attenuate the reinforcing effects of nicotine in females to a greater extent than in males. Steroid hormone receptor antagonists will be used to determine the hormone specificity of behavioral effects observed. Finally, the reinforcing effects of gonadal steroid hormones alone will be compared in males and females before and after gonadectomy. The neuroactive steroid hormones provide a novel approach to the treatment of a number of psychiatric disorders as well as drug abuse. The proposed studies may translate into new and more effective approaches to the treatment of nicotine addiction and will advance our understanding of its basic neurobiology. PUBLIC HEALTH RELEVANCE: Addiction to cigarette smoking is a major public health problem that is associated with many debilitating and lethal disorders (lung cancer, stroke, cardiovascular and respiratory disease, osteoporosis), yet effective treatments remain elusive. We propose to study how sex and neuroactive gonadal steroids influence the abuse-related effects of nicotine (the main addictive component of tobacco) in males and females. We hypothesize that the neuroactive gonadal steroid hormones may offer a novel biologic approach to the treatment of nicotine addiction, in part because these neuroactive hormones are being used to treat a number of psychiatric disorders, including depression and anxiety, and may have therapeutic applications in drug dependence.